EDITORS:
The study, Role of Melanopsin in Circadian
Responses to Light, will be published in the
Dec. 13 issue of Science. A copy of the
study can be obtained by contacting the AAAS Office
of Public Programs at (202) 326-6440 or
scipak@aaas.org.

Scientists
shed new light on the body's internal clock

As
mammals, our internal (circadian) clock is regulated
by the patterns of light and dark we experience. But
how that information is transmitted from the eye to
the biological clock in the brain has been a matter
of scientific debate. Scientists had suspected that a
molecule called melanopsin, which is found in the
retina, plays an important role.

Now
researchers at Stanford University and Deltagen Inc.
have confirmed that melanopsin does indeed transmit
light information from the eye to the part of the
brain that controls the internal clock. According to
the researchers, melanopsin may be one of several
photosensitive receptors that work redundantly to
regulate the circadian system.

"This
study clarifies the role of melanopsin in setting and
maintaining the circadian clock," said Bruce
O'Hara, senior research scientist at Stanford and
co-author of the study published in the Dec. 13 issue
of the journal Science.

O'Hara
noted that without a circadian clock many behavioral
and physiological traits of mammals would be
disturbed -- including body temperature, activity
levels and sleep.

"Instead
of being able to sleep for extended periods of time,
we would be at the mercy of unpredictable bursts of
sleep and activity," added Stanford senior
research scientist Norman Ruby, lead author of the
study.

Photoreceptors

For a
circadian clock to function, it must be able to
detect and respond to light. In mammals, the only
cells specialized to do this are in the eyes, which
means that our eyes not only allow us to see the
world but also synchronize our body's internal
rhythms.

Photoreceptors
are specialized cells that can detect light and send
signals to the brain, which then processes and
interprets the information -- allowing us to see.
Rods and cones, which are located in the retina, are
the primary photoreceptors for vision. Researchers
first thought that these molecules had dual roles in
vision and setting the circadian clock. But
experiments showed that animals lacking rods or cones
could still modify their internal clocks in response
to changing light conditions. This led scientists to
hunt for an alternate photoreceptor that could
regulate the circadian system.

Melanopsin,
a molecule originally found in frog skin, was the
most likely suspect. Scientists discovered that
melanopsin molecules in frog skin cells sense and
respond to light. The molecule later was found in
frog and mouse retinas, and complementary studies
determined that cells containing melanopsin send
signals to different parts of the brain -- further
evidence of the molecule's potential role in setting
the circadian clock.

The only
test that remained was to determine if the circadian
clock could function without melanopsin. To
accomplish that, Ruby and O'Hara teamed up with
Deltagen Inc., a company based in Redwood City,
Calif., that specializes in deleting specific genes
from mice. Deltagen deleted (or "knocked
out") the melanopsin gene in mice. The Stanford
group then used the knockout mice to determine the
relative role of melanopsin in transmitting light
information to the circadian system.

Lowered
response

In their
Science study, the researchers found that the
circadian system in melanopsin-depleted knockout mice
had a 40 percent decrease in their ability to respond
to changes in light intensity compared with normal
mice. This result led the scientists to conclude
that, although melanopsin is important, it is not the
only molecule involved in setting the circadian
clock.

"Melanopsin
is one of the key players, but it is not the only
player," Ruby and O'Hara explained, noting that
the knockout mice, which lacked melanopsin, continued
to respond to new light patterns, albeit less
efficiently. The researchers concluded that the eye
and the brain probably have redundant systems that
contribute to regulating and resetting the circadian
clock. Such redundancy would be evolutionarily
advantageous, they added.

"Deltagen
is very pleased with the work flowing from our
collaboration with Stanford, and we commend the
scientists involved in this study on their work to
further elucidate the role of melanopsin in the sleep
cycle," said Mark Moore, chief scientific
officer of Deltagen Inc. "We believe that our
company's high throughput gene knockout approach,
coupled with our comprehensive systems biology
analysis program, will continue to be instrumental in
leading researchers to gene function -- and
ultimately to new pharmaceutical targets and drug
candidates."

While
the Science study confirms that melanopsin can
transmit information to the circadian clock, future
studies will focus on identifying the relative
contributions of other molecules to circadian clock
maintenance, Ruby and O'Hara noted.

Other
co-authors of the Science study are Thomas J.
Brennan and Ximmin Xie of Deltagen, and Vinh Cao,
Paul Franken and H. Craig Heller of the Department of
Biological Sciences at Stanford. This project was
funded by the National Institutes of Health and
Deltagen.

Caroline
Uhlik is a science-writing intern at the Stanford
News Service.